9-aminotetrahydroacridines and related compounds

ABSTRACT

The present invention relates to 9-amino-1,2,3,4-tetrahydroacridines and related compounds of formula 1 &lt;CHEM&gt; wherein Y ix C=0 or CHOH; R&lt;1&gt; is hydrogen or loweralkyl; R&lt;2&gt; is hydrogen, loweralkyl, or phenylloweralkyl; R&lt;3&gt; is hydrogen, OR&lt;4&gt; wherein R&lt;4&gt; is hydrogen or COR&lt;5&gt; wherein R&lt;5&gt; is loweralkyl, X is hydrogen, loweralkyl, halogen, loweralkoxy, hydroxy, or trifluoromethyl, the geometric or optical isomers thereof, N-oxides, thereof, or the pharmaceutically acceptable acid addition salts thereof, which are useful in relieving memory dysfunction and are thus indicated in the treatment of Alzheimer&#39;s disease. The invention relates further to a process for the preparation of the above compounds.

The present invention relates to 9-aminotetrahydroacridines and relatedcompounds. More particularly, the present invention relates to9-amino-1,2,3,4-tetrahydroacridines and related compounds of formula 1##STR1## wherein Y is C═O or CHOH; R¹ is hydrogen or loweralkyl; R² ishydrogen, loweralkyl, or phenylloweralkyl; R³ is hydrogen, OR⁴ whereinR⁴ is hydrogen, COR⁵ wherein R⁵ is loweralkyl; X is hydrogen,loweralkyl, halogen, loweralkoxy, hydroxy, or trifluoromethyl, thegeometric or optical isomers thereof, the N-oxides thereof, or thepharmaceutically acceptable acid addition salts thereof, which areuseful in relieving memory dysfunction and are thus indicated in thetreatment of Alzheimer's disease.

Preferred 9-amino-1,2,3,4-tetrahydroacridines and related compounds ofthe present invention are those wherein Y is C═O or CHOH and R³ is OR⁴wherein R⁴ is hydrogen.

The present invention also relates to 9-aminosilyldihydroacridinones offormula 2 ##STR2## wherein R¹ is hydrogen or loweralkyl, R² is hydrogen,loweralkyl, or phenylloweralkyl, R⁶ is phenyl or fluoro; and X ishydrogen, loweralkyl, halogen, loweralkoxy, hydroxy, or trifluoromethyland dihydrobenzisoxazolines of formula 3 ##STR3## wherein X is hydrogen,loweralkyl, halogen, loweralkoxy, hydroxy, or trifluoromethyl, which areuseful as intermediates for the preparation of the9-aminoetrahydroacridindiols and related compounds of the presentinvention.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 8 carbon atoms. Examples ofalkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl,3-hexyl, 4-heptyl, 2-octyl and the like. The term "alkoxy" refers to amonovalent substituent which consists of alkyl group linked through anether oxygen having its free valence bond from the ether oxygen.Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butoxy,1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy and the like. The term"alkanol" refers to a compound formed by a combination of an alkyl groupand hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol and the like. The term"alkanoic acid" refers to a compound formed by combination of a carboxylgroup with a hydrogen atom or alkyl group. Examples of alkanoic acidsare formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid,hexanoic acid, octanoic acid and the like. The term "halogen" refers toa member of the family fluorine, chlorine, bromine, or iodine. The term"alkanoyl" refers to the radical formed by removal of the hydroxyfunction from an alkanoic acid. Examples of alkanoyl groups are formyl,acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl andthe like. The term "alkanoic acid anhydride" refers to a compound formedby combination of two alkanoyl radicals and one oxy radical. Examples ofalkonoic acid anhydrides are acetic acid anhydride, propanoic acidanhydride, 2,2-dimethylacetic acid anhydride, hexanoic acid anhydride,octanoic acid anhydride and the like. The term "lower" as applied to anyof the aforementioned groups refers to a group having a carbon skeletoncontaining up to and including 6 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

In the formulas of the 9-aminotetrahydroacridindiols presented hereinthe hydroxyl groups attached to the cyclohexane ring system may beeither in the cis or trans configuration, i.e., the hydroxyl groups maybe, respectively, on the same side or on opposite sides of the averageplane of the cyclohexane ring. Unless otherwise specified, each formulacontemplates both the cis and trans isomers. In the structural formulaused herein, heavy lines ( ) indicate that the substituent is above theaverage plane of the cyclohexane ring and broken lines ( ) indicate thatthe substituent is below the average plane of ring. A wavy line ( )indicates the substituent may be above or below the average plane of thering.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted.

The novel 9-aminotetrahydroacridindiols of the present convention areprepared by the processes delineated in Reaction Schemes A and B.

To prepare a 9-amino-1,2,3,4-tetrahydroacridin-1,4-diol 9 of the presentinvention, a 2-nitrobenzhydroxamic chloride 4 is condensed with acyclohexan-1,3-dione enamine 5 to provide a6,7-dihydro-3-(2-nitrophenyl)benzisoxazol-4(5H)-one 6 which isreductively cyclized to a 9-amino-3,4-dihydroacridin-1(2H)-one N-oxide7, rearranged to a 4-alkanoyloxy-9-amino-3,4-dihydroacridin-1(2H)-one 8,and reduced and cleaved to a diol 9. See Reaction Scheme A.

The condensation of a hydroxamic acid chloride 4 with an enamine 5(e.g., an enamine where R⁸ and R⁹ are alkyl, or together form aheterocycle such as morpholine) to a benzisoxazole 6 is performed in anethereal solvent such as 1,2-dimethoxylethane, 2-methoxyethyl ether,dioxane, and tetrahydrofuran, tetrahydrofuran being preferred. While thecondensation temperature is not narrowly critical, it is preferred toperform the reaction at the reflux temperature of the reaction medium.

The reductive cyclization of a benzisoxazolone 6 to an aminoacridinoneN-oxide 7 is conducted by hydrogenating benzisoxazole 6 in the presenceof a catalyst under acidic conditions in an ethereal solvent. Amongcatalysts, there may be mentioned platinum, palladium, rhodium andruthenium, unsupported or supported on, for example, carbon, alumina, orcalcium carbonate. Palladium-on-carbon is preferred. Included amongethereal solvents are 1,2-dimethoxyethane, 2-methoxyethyl ether,dioxane, and tetrahydrofuran. Tetrahydrofuran is preferred. Acidicreaction conditions are obtained by conducting the reaction in dilutemineral acid, i.e. dilute hydrochloric, hydrobromic, nitric, orphosphoric acid. 5% Hydrochloric acid is preferred. Under theseconditions, the hydrogenation proceeds at a reasonable rate under ahydrogen pressure within the range of about atmospheric pressure toabout 100 psi. A hydrogenation pressure of about 50 psi is preferred.

The rearrangement of an acridinone N-oxide 7 to a4-alkanoyloxyacridinone 8 is effected by means of an alkanoic acidanhydride of formula 16

    (R.sup.5 CO).sub.2 O                                       16

wherein R⁵ is alkyl, the anhydride 16 acting as a reactant and thereaction solvent. The preferred anhydride is acetic anhydride. Therearrangement proceeds readily at the reflux temperature of the medium;reduced rearrangement temperatures to as low as ambient temperature maybe employed, however.

The reduction and cleavage are carried out by treating a4-alkanoyloxy-9-aminoacridinone 8 with an alkali metal aluminum hydride,for example, lithium, sodium, or potassium aluminum hydride, in anethereal solvent, for example, diethyl ether, 1,2-dimethoxyethane,2-methoxyethyl ether, dioxane, or tetrahydrofuran. Lithium aluminumhydride and tetrahydrofuran are the preferred alkali metal hydride andethereal solvent, respectively. The temperature at which the reductionand cleavage are preformed is not critical; however, it is preferred toperform the reaction at about ambient temperature. Under theaforedescribed conditions, a mixture of the cis- and trans-acridindiols9a and 9b, respectively is formed, which is separated by flashchromatography. ##STR4##

To gain entry into the 9-amino-1,2,3,4-tetrahydroacridin-1,3-diolseries, i.e., to prepare diols of formula 15, an anthranilonitrile 10 iscondensed with a 5-(phenyldialkylsilyl)-1,3-cyclohexanedione 11 toafford a 3-(oxocyclohex-1-enyl)-2-aminobenzonitrile 12, which iscyclized to a 9-amino-3-(phenyldialkylsilyl)acridinone 13 and, in turn,converted to a 9-amino-3-hydroxyacridinone 14 and reduced to a diol 15.

The condensation of an aniline 10 with a dione 11 to enaminone 12 isconveniently conducted in the presence of an acid catalyst in anaromatic solvent at the boiling point of the reaction medium with watercollection in a Dean-Stark apparatus. Acid catalysts include mineralacids (e.g., sulfuric acid) and organic sulfonic acids (e.g.,methanesulfonic acid, benzenesulfonic acid, and para-toluenesulfonicacid). Aromatic solvents include benzene, toluene, xylene, andmesitylene. The preferred condensation medium consists ofpara-toluenesulfonic acid and toluene.

The cyclization of an enaminone 16 to a 9-aminoacridinone 13 is achievedin an ethereal solvent (e.g., 1,2-dimethoxyethane, 2-methoxyethyl ether,dioxane, or tetrahydrofuran) containing a base (e.g., an alkali metalcarbonate such as lithium, sodium, or potassium carbonate) and apromoter (e.g., a cuprous halide such a cuprous bromide or chloride).Preferred among the ethereal solvents, bases, and promoters aretetrahydrofuran, potassium carbonate, and cuprous chloride,respectively. While the cyclization proceeds at a reasonable rate atabout ambient temperature, to expedite the transformation, elevatedreaction temperatures to the reflux temperature of the medium may beemployed. The preferred cyclization temperate is the reflux temperatureof the reaction medium.

The conversion of a 3-(phenyldialkylsilyl)acridinone 13 to a3-hydroxyacridinone 14 is effected by fluorination of 13 wherein R¹¹ isphenyl to a 3-(fluorodialkylsilyl)acridinone 13 wherein R¹¹ is fluorofollowed by oxidative cleavage of the silyl group. The fluorination isaccomplished in a halocarbon (e.g., dichloromethane, trichloromethane,or 1,1- or 1,2-dichloroethane) in the presence of tetrafluoroboric acidor its etherate at about ambient temperature.

The oxidative cleavage is accomplished by means of hydrogen peroxide inan ether/alkanol solvent in the presence of an alkali fluoride (e.g.,lithium, sodium, or potassium fluoride) and an alkali bicarbonate (e.g.,lithium, sodium, or potassium bicarbonate) at a reaction temperature ofabout 0° to about 25° C. Among ethereal components of the solvent, theremay be mentioned 1,2-dimethoxymethane, 2-methoxy ethyl ether, dioxane,tetrahydrofuran, and mixtures thereof. Among alkanol components, theremay be mentioned methanol, ethanol and 1-, or 2-propanol.Tetrahydrofuran/methanol is the preferred solvent. Potassium fluorideand sodium bicarbonate are the preferred alkali fluoride and alkalibicarbonate, respectively. It is also preferable to perform theoxidative cleavage initially at about 0° C. and finally at about 25° C.

The reduction of a 9-amino-3-hydroxyacridin-1(2H)-one 14 to a9-aminoacridindiol 15 is conducted in an ethereal solvent (e.g., diethylether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, ortetrahydrofuran) by means of an alkali metal trialkylborohydride offormula 17 (e.g., lithium, sodium, or potassium trimethyl, triethyl,tri-1- or 2-propylborohydride) at about ambient temperature. Lithiumtriethylborohydride in tetrahydrofuran is the preferred reductionmedium. Under the aforedescribed conditions, a mixture of the cis- andtrans-acridindiols 15a and 15b, respectively is formed, which isseparated by flash chromatography. ##STR5##

A 9-aminoacridin-1,2-diol 18 may be prepared from a 2-aminobenzonitrile10 and a 6-(phenyldialkylsilyl)-1,3-cyclohexandione 19 by following theprocesses shown in Reaction Scheme B. ##STR6##

Alkylation of the amino group of the 9-aminoacridindiols and derivativesthereof, 9-aminohydroxyacridinones and 9-aminosilylacridinones of thepresent invention, i.e., compounds of the formulas 8,9,13,14, and 15 toprovide 9-alkylamino- and 9-dialkylaminoacridindiols,-1-hydroxyacridinones, and -silylacridinones, may be preformed byutilizing conventional processes.

The 9-aminotetrahydroacridines of the present invention are useful asagents for the relief of memory dysfunction, particularly dysfunctionsassociated with decreased cholinergic activity such as those found inAlzheimer's disease. Relief of memory dysfunction activity of theinstant compounds is demonstrated in the dark avoidance assay, an assayfor the determination of the reversal of the effects of scopolamineinduced memory deficits associated with decreased levels ofacetylcholine in the brain. In this assay, three groups of 15 male CFWmice were used--a vehicle/vehicle control group, a scopolamine/vehiclegroup, and a scopolamine/drug group. Thirty minutes prior to training,the vehicle/vehicle control group received normal saline subcutaneously,and the scopolamine/vehicle and scopolamine/drug groups receivedscopolamine subcutaneously (3.0 mg/kg, administered as scopolaminehydrobromide). Five minutes prior to training, the vehicle/vehiclecontrol and scopolamine/vehicle groups received distilled water and thescopolamine/drug group received the test compound in distilled water.

The training/testing apparatus consisted of a plexiglass boxapproximately 48 cm long, 30 cm high and tapering from 26 cm wide at thetop to 3 cm wide at the bottom. The interior of the box is dividedequally by a vertical barrier into a light compartment (illuminated by a25-watt reflector lamp suspended 30 cm from the floor) and a darkcompartment (covered). A hole (2.5 cm wide and 6 cm high) at the bottomof the barrier and a trap door that can be dropped to prevent an animalfrom passing between the two compartments is present. A CoulbournInstruments small animal shocker was attached to two metal plates thatran the entire length of the apparatus, and a photocell was placed inthe dark compartment 7.5 cm from the vertical barrier and 2 cm above thefloor. The behavioral session was controlled by a PDP 11/34minicomputer.

At the end of the pretreatment interval, an animal was placed in thelight chamber directly under the light fixture, facing away from thedoor to the dark chamber. The apparatus was then covered and the systemactivated. If the mouse passed through the barrier to the darkcompartment and broke the photocell beam within 180 seconds, the trapdoor dropped to block escape to the light compartment and an electricshock was administered at an intensity of 0.4 milliamps for threeseconds. The animal was then immediately removed from the darkcompartment and placed in its home cage. If the animal failed to breakthe photocell beam within 180 seconds, it was discarded. The latency isseconds for each mouse was recorded.

Twenty-four hours later, the animals were again tested in the sameapparatus except that no injections were made and the mice did notreceive a shock. The test day latency in seconds for each animal wasrecorded and the animals were then discarded.

The high degree of variability (due to season of the year, housingconditions, and handling) found in one trial passive avoidance paradigmis well known. To control for this fact, individual cutoff (CO) valueswere determined for each test, compensating for interest variability.Additionally, it was found that 5 to 7% of the mice in thescopolamine/vehicle control groups were insensitive to scopolamine at 3mg/kg, sc. Thus, the CO value was defined as the second highest latencytime in the control group to more accurately reflect the 1/15 expectedcontrol responders in each test group. Experiments with a variety ofstandards repeated under a number of environmental conditions led to thedevelopment of the following empirical criteria: for a valid test, theCO value had to be less than 120 sec and the vehicle/vehicle controlgroup had to have at least 5/15 animals with latencies greater than CO.For a compound to be considered active the scopolamine/compound grouphad to have at least 3/15 mice with latencies greater than CO.

The results of the dark avoidance test are expressed as the number ofanimals per group (%) in which this scopolamine induced memory deficitis blocked as measured by an increase in the latency period. Relief ofmemory dysfunction activity for representative compounds of the presentinvention is presented in the Table 1.

                  TABLE 1                                                         ______________________________________                                                       Dose     Percent of Animals with                                              (mg/kg,  Scopolamine Induced                                   Compound       sc)      Memory Deficit Reversal                               ______________________________________                                        9-amino-1,2,3,4-                                                                             3.0      27                                                    tetrahydro-1,3-acridinediol                                                   maleate, mp 158-160° C.                                                9-amino-1,2,3,4-                                                                             3.0      20                                                    tetrahydro-1,3-acridinediol                                                   maleate, mp 179-180° C.                                                9-amino-1,2,3,4-                                                                             3.0      21                                                    tetrahydro-1,4-acridinediol,                                                  mp 200° C. (dec)                                                       physostigmine  0.31     20                                                    ______________________________________                                    

Scopolamine induced memory deficit reversal is achieved when the present9-aminotetrahydroacridines are administered to a subject requiring suchtreatment as an effective oral, parenteral or intravenous dose of from0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 25 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.

The 9-aminotetrahydroacridines of the present invention exhibit lowtoxicity (lethality) as determined in the primary overt effects assay.In this assay, groups of four male Wistar rats (125-300 g) are used.Prior to testing, the animals are housed for at least 24 hrs in aclimate controlled room with food and water available ad libitum. On theday of testing, the animals are removed from their home cages and placed4/box in white translucent plastic boxes (45×25×29 cm) with metal barcovers and transported to the test room. Food and water are notavailable at any time during the day of testing.

Compounds are prepared using distilled water and, if insoluble, asurfactant is added and the resulting suspension is kept constantlyagitated.

Prior to drug administration, all animals are examined for any overtabnormalitities which may subsequently be confused as a drug effect.These include eye position, eye clarity, blood around eyes or nose,unusual gait, abnormal behavior during handling and abnormal behavior inthe plastic boxes. Core temperatures are then determined (eitherrectally or intraperitoneally).

Animals are then administered drug intraperitoneally with the controlgroup receiving vehicle.

Animals are observed in the plastic boxes continuously for one hourafter drug administration and any overt effects are noted. A completeexamination is made on each animal at 1,2,4 and 6 hrs postdrug and theresults are recorded. The room should be quiet during testing. Obviouseffects seen between these times are recorded. The animals are givenfood and water after 6 hours and kept for 24 hrs, when their generalcondition is observed. Time of death is noted for each animal and thetime at which the first and last deaths occur are reported.

The results are expressed as the number of deaths per group. Toxicity ofrepresentative compounds of the present invention is presented in Table2.

                  TABLE 2                                                         ______________________________________                                                       Dose       Number of Deaths                                    Compound       (mg/kg, sc)                                                                              per Group                                           ______________________________________                                        9-amino-1,2,3,4-                                                                             80         0                                                   tetrahydro-1,3-acridinediol                                                   maleate, mp 158-160° C.                                                9-amino-1,2,3,4-                                                                             80         0                                                   tetrahydro-1,3-acridinediol                                                   maleate, mp 179-180° C.                                                9-amino-1,2,3,4-tetrahydro-                                                                  80         0                                                   1,4-acridinediol,                                                             mp 200° C. (dec)                                                       ______________________________________                                         Compounds of the invention include:                                           a. 9methylamino-1,2,3,4-tetrahydro-1,4-acridinediol;                          b. 9(2-phenylethylamino)-1,2,3,4-tetrahydro-1,4-acridinediol;                 c. 9amino-8-methyl-1,2,3,4-tetrahydro-1,4-acridinediol;                       d. 9amino-7-fluoro-1,2,3,4-tetrahydro-1,4-acridinediol;                       e. 9amino-6-methoxy-1,2,3,4-tetrahydro-1,4-acridinediol;                      f. 9amino-6-hydroxy-1,2,3,4-tetrahydro-1,4-acridinediol;                      g. 9amino-5-trifluoromethyl-1,2,3,4-tetrahydro-1,4-acridinediol;              h. 9amino-7-fluoro-3,4-dihydroacridin-1(2H)-one;                              i. 9amino-6-methoxy-3,4-dihydroacridin-1(2H)-one;                             j  9amino-6-hydroxy-3,4-dihydroacridin-1(2H)-one; and                         k. 9amino-5-trifluoromethyl-3,4-dihydroacridin-1(2H)-one.                

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The basic final products and intermediates, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1 6,7-Dihydro-3-(2-nitrophenyl)-1,2-benzisoxazol-4(5H)-one

To a solution of 1,3-cyclohexadione morpholine enamine (20.8 g),tetrahydrofuran (150 ml), and triethylamine (2 ml) at reflux was added asolution of 2-nitrobenzhydroxamic chloride (17.7 g) in tetrahydrofuran(100 ml) dropwise over 2 hrs. The reaction mixture was heated underreflux for 1 hr and then evaporated. The residue was partitioned between3N hydrochloric acid and ethyl acetate. The ethyl acetate layer waswashed with 3N hydrochloric acid, 10% sodium carbonate solution,saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The reside waschromatographed on silica gel with ethyl acetate as the eluent. Theappropriate fractions were collected and evaporated. The residue wasrecrystallized from dichloromethane/hexanes to yield 15.0 g (66%) ofproduct, mp 125°-127° C.

Analysis: Calculated for C₁₃ H₁₀ N₂ O₄ : 60.47% C; 3.90% H; 10.85% N.Found: 60.81% C; 4.13% H; 10.88% N.

EXAMPLE 2 9-Amino-3,4-dihydroacridin-1(2H)-one N-oxide

A mixture of 6,7-dihydro-3-(2-nitrophenyl)-1,2-benzisoxazole-4(5H)-one,(7.0 g), 5% palladium-on-carbon (0.7 g), 5% hydrochloric acid (11 ml),and tetrahydrofuran (200 ml) was hydrogenated at 50 psi. After one hr,methanol (1 l) was added, and the mixture was filtered through celite.The filtrate was concentrated, and the concentrate was flashchromatographed (silica, 3-20% methanol/ethyl acetate; 40%methanol/dichloromethane). The appropriate fractions were collected andconcentrated. The residue was triturated with methanol/diethyl ether toyield 5.4 g (83%) of product, mp 290° C. (dec).

EXAMPLE 3 4-acetoxy-9-amino-3,4-dihydroacridin-1(2H)-one

A solution of 9-amino-3,4-dihydroacridin-1(2H)-one N-oxide (5.4 g) andacetic anhydride (60 ml) was heated to reflux and then concentrated. Theresidue was stirred in saturated sodium bicarbonate solution for one hr.The mixture was filtered and the filter cake was washed with water anddried under vacuum at 40° C. for three hrs to yield 1.93 g of product,mp 208° C. (dec). An additional 1.38 g, mp 208° C. (dec), of product wasobtained by extraction of the filtrate with ethyl acetate, evaporationof ethyl acetate extract, and trituration of the residue with diethylether; total 52% yield.

EXAMPLE 4 9-Amino-1,2,3,4-tetrahydro-1,4-acridinediol

To a solution of 3-acetoxy-9-amino-3,4-dihydroacridin-1(2H)-one (1.5 g)in dry tetrahydrofuran (75 ml), was added lithium aluminum hydride (1.0Min tetrahydrofuran, 11.1 ml) dropwise, with stirring. Stirring wascontinued for 15 mins. The reaction mixture was quenched with methanol,concentrated, and the residue was flash chromatographed (silica, 3:10:87methanol:triethylamine:dichloromethane). The appropriate fractions werecollected and evaporated.

An additional experiment was run on the same scale. The fractions werecombined and distributed between methyl ethyl ketone and 10% sodiumhydroxide solution. The organic fraction was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated undervacuum. Recrystallization of the residue of the more polar fractionsfrom water/methanol yielded 800 mg (31%) of9-amino-1,2,3,4-tetrahydro-1,4-acridinediol, mp 200° C.(dec).

Analysis: Calculated for C₁₃ H₁₄ N₂ O₂ : 67.81% C; 6.13% H; 12.17% N.Found: 67.72% C; 6.28% H; 12.11% N.

Recrystallization of the residue of the less polar fractions from watergave 304 mg (11.9%) of 9-amino-1,2,3,4-tetrahydro-1,4-acridinediol, mp183° C. (dec).

Analysis: Calculated for C₁₃ H₁₄ N₂ O₂ : 67.81%C; 6.13% H; 12.17% N.Found: 67.62% C; 6.33% H; 12.06% N.

EXAMPLE 5N-[5-(Phenyldimethylsilyl)-3-oxocyclohex-1-enyl]-2-aminobenzonitrile

A solution of anthranilonitrile (3.33 g), and5-(phenyldimethylsilyl)-1,3-cyclohexanedione (6.61 g), and toluene (180ml) containing 0.51 g of p-toluenesulfonic acid monohydrate was heatedunder reflux with collection of water in a Dean-Stark trap. After 3 hr,the reaction mixture was diluted with ethyl acetate, and the solutionwas washed with saturated sodium bicarbonate solution and water, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed on silica gel, elutingwith dichloromethane and then, successively 5%, 10%, and 15% ethylacetate in dichloromethane. The appropriate fractions were collected andevaporated to give 6.37 g (68%) of product, mp 126°-129° C.

EXAMPLE 6 9-Amino-3,4-dihydro-3-(phenyldimethylsilyl)acridin-1(2H)-one

A mixture ofN-[5-(phenyldimethylsilyl)-3-oxocyclohex-1-enyl]-2-aminobenzonitrile(6.3 g) in tetrahydrofuran (180 ml) containing potassium carbonate (2.76g) and cuprous chloride (0.18 g) was refluxed for 4 hrs. The reactionmixture was diluted with methanol (100 ml) and then flushed over acolumn of Florisil. The appropriate fractions were collected andevaporated to give 5.05 g (80%) of product, mp 178°-180° C.

EXAMPLE 7 9-Amino-3,4-dihydro-3-(fluorodimethylsilyl)acridin-1(2H)-one

A mixture of9-amino-3,4-dihydro-3-(phenyldimethylsilyl)acridin-1(2H)-one (5.0 g),dichloromethane (80 ml) and tetrafluoroboric acid etherate (25 ml) wasstirred overnight at ambient temperature. The reaction mixture waspoured into saturated potassium carbonate solution and extracted withethyl acetate. The suspension was filtered through celite and theorganic phase was separated. The aqueous phase was extracted with ethylacetate and the combined organic phases were dried over anhydrousmagnesium sulfate, filtered, and the filtrate evaporated to give 3.79 g(90%) of product, which is used in Example 8 without purification andwithout delay.

EXAMPLE 8 9-Amino-3,4-dihydro-3-hydroxyacridin-1(2H)-one

A solution 9-amino-3,4-dihydro-3-(fluorodimethylsilyl)acridin-1(2H)-one(3.7 g) 1:1-tetrahydrofuran:methanol (70 ml), potassium fluoride (7.45g), and sodium bicarbonate (10.7 g) was chilled in an ice/water bath,and 30% aqueous hydrogen peroxide (44 ml) was added slowly. Uponcompletion of the addition, the bath was removed and stirring wascontinued for 3 hr. The reaction mixture was poured into water (250 ml)and a little diethyl ether was added. The mixture was filtered and thefilter cake was washed with water and diethyl ether to give 2.6 g (89%)of product, mp 205° C. (dec).

EXAMPLE 9 9-Amino-1,2,3,4-tetrahydro-1,3-acridinediol maleate

A suspension of 9-amino-3,4-dihydro-3-hydroxyacridin-1(2H)-one (2.07 g)in tetrahydrofuran (125 ml), lithium triethylborohydride (1 molar intetrahydrofuran, 27 ml) was allowed to stand for 0.5 hrs. The reactionmixture was quenched with methanol. The mixture was preadsorbed onsilica, and flash chromatographed on silica gel(1:2:17-dichloromethane:triethylamine). The appropriate fractions werecollected. Evaporation of the more polar fractions gave 0.541 (25.8%) of9-amino-1,2,3,4-tetrahydro-1,3-acridinediol, mp 139°-141° C.

9-Amino-1,2,3,4-tetrahydro-1,3-acridinediol (mp 139°-141° C.) wasdissolved in methanol and treated with maleic acid (1.1 eq.). Diethylether was added and the precipitate was collected to give the maleate,mp 158°-160° C.

Analysis: Calculated for C₁₃ H₁₄ N₂ O₂.C₄ H₄ O₄ : 58.96% C; 5.24% H;8.09% N. Found: 58.72% C; 5.27% H; 7.99% N.

Evaporation of the less polar fractions gave 0.784 g (37.3%) of9-amino-1,2,3,4-tetrahydro-1,3-acridinediol, mp 158°-162° C. The maleatehad mp 179°-180° C.

Analysis: Calculated for C₁₃ H₁₄ N₂ O₂.C₄ H₄ O₄ : 58.96% C; 5.24% H;8.09% N. Found: 58.95% C; 5.28% H; 8.15% N. ##STR7##

We claim:
 1. A compound of the formulawherein Y is C═O; R¹ is hydrogen or loweralkyl; R² is hydrogen, loweralkyl, or phenylloweralkyl; R³ is OR⁴ wherein R⁴ is hydrogen, COR⁵ wherein R⁵ is loweralkyl, X is hydrogen, loweralkyl, halogen, loweralkoxy, hydroxy, or trifluoromethyl, the geometric or optical isomers thereof, N-oxides thereof, or the pharmaceutically acceptable acid addition salts thereof.
 2. A compound according to claim 1 wherein Y is C═O and R³ is OR⁴ wherein R⁴ is hydrogen.
 3. The compound according to claim 2 which is 3-acetoxy-9-amino-3,4-dihydroacridin-1(2H)-one.
 4. The compound according to claim 3 which is 9-amino-1,2,3,4-tetrahydro-1,4-acridinediol, having a melting point of 200° C. (dec).
 5. The compound which is 9-amino-3,4-dihydroacridin-2(2H)-one N-oxide.
 6. A method of relieving memory dysfunction in mammals comprising administering to a mammal requiring memory dysfunction relief, a memory dysfunction relieving effective amount of a compound of claim
 1. 7. A memory of dysfunction relieving composition comprising and adjuvant and as the active ingredient, a memory dysfunction relieving effective amount of a compound of claim
 1. 